Particles that release a therapeutic payload upon interaction with an internal stimulus, such as pH or hypoxia, or the application of an externally-applied stimulus, such as heat or ultrasound (US), are being studied in an effort to localize drug delivery to target areas [Dayton et al., Mol Imaging. 5(3): 160-174 (2006); Ganta et al., J Control Release. 126(3): 187-204 (2008); Laing et al., J Liposome Res. 20(2): 160-167 (2010); Rapoport, Prog Polym Sci. 32(8): 962-990 (2007); Unger et al., Adv Drug Deliv Rev. 56(9):1291-1314 (2004)]. The control of localized delivery is especially important for drugs that possess narrow therapeutic windows, thereby minimizing systemic side-effects. The interaction of US with payload-containing particles can generate acoustic cavitation, heating, radiation forces, and sonoporation. The last effect, the transient increase in cell membrane permeability, can greatly enhance the uptake of drugs, genes, and peptides contained within US-activated particles [Eisenbrey et al., J Control Release. 143(1): 38-44 (2010); Lentacker et al., Mol Ther. 18(1): 101-108 (2010); Liang et al., Proc Inst Mech Eng H. 224(H2): 343-361 (2010); Ren et al., Acad Radiol. 16(12):1457-1465 (2009)]. These particle-US interactions can also produce therapeutic effects to be utilized in diverse applications such as thrombolysis [Datta et al., Ultrasound Med Biol. 34(9): 1421-1433 (2008)] or in the reversible disruption of the blood-brain barrier [Yang et al., J Acoust Soc Am. 126(6): 3344-3349 (2009)].
Colloidal particles utilized in US-mediated drug release are typically shell-stabilized microbubbles or droplets containing, respectively, perfluorocarbon (PFC) gases or liquids. The former colloids evolved from clinically-utilized US contrast agents, which are micron-sized gas bubbles that increase the echogenicity in perfused tissue upon intravenous administration. Due to their size, the microbubbles are transpulmonary and resonant at frequencies utilized in clinical imaging systems [Dayton et al., J Magn Reson Imaging. 16(4): 362-377 (2002)]. Therapeutic agents are typically incorporated into the microbubbles using one of the following methods: attachment to or intercalation within the shell; complexation of secondary carriers to the microbubble shell; or incorporation within a fluid inside the shell [Hernot et al., Adv Drug Deliv Rev. 60(10): 1153-1166 (2008); Tinkov S, Bekeredjian R, Winter G, Coester C. Microbubbles as ultrasound triggered drug carriers. J Pharm Sci. 98(6):1935-1961 (2009)].
As highlighted in a recent review [Diaz-Lopez et al., Pharm Res. 27(1): 1-16 (2010)], PFC emulsions have also been studied as US contrast agents and drug delivery systems due to their increased stability, longer circulation times, and ability to extravasate if formulated as nanoparticles. Due to the hydrophobicity and lipophobicity of the dispersed PFC phase [Riess, Chem Rev. 101(9): 2797-2919 (2000], therapeutic agents are typically loaded into the emulsion using similar techniques as those mentioned for microbubble delivery systems. One commonly utilized method is the use of an oil-phase, containing the therapeutic agent, co-emulsified with the PFC phase during formulation [Fabiilli et al., Ultrasound Med Biol. 36(8): 1364-1375 (2010); Fang et al., Eur J Pharm Biopharm. 67(1): 67-75 (2007); Fang et al., Ultrasonics. 49(1): 39-46 (2009); Hwang et al., J Pharm Sci. 98(10): 3735-3747 (2009)]. PFC emulsions, with or without a therapeutic payload, can be vaporized into gas bubbles using US, a mechanism termed acoustic droplet vaporization (ADV) [U.S. Pat. No. 5,840,276; Giesecke et al., Ultrasound in Medicine and Biology. 29(9): 1359-1365 (2003); Kripfgans et al., Ultrasound Med Biol. 26(7): 1177-1189 (2000); Kawabata et al., Jpn J Appl Phys. 44(6B): 4548-4552 (2005); Rapoport et al., J Control Release. 138(3): 268-276 (2009)]. ADV is a phenomenon whereby vaporization occurs only if the emulsion is exposed to acoustic amplitudes greater than a threshold value. PFCs used in emulsions suitable for ADV applications typically possess bulk boiling points that are lower than normal body temperature (37° C.), such as perfluoropentane (29° C. boiling point). Upon injection in vivo, the emulsions do not spontaneously vaporize due to the increased internal (i.e., Laplace) pressure, and hence boiling point elevation, of the PFC when formulated as droplets [Rapoport et al., J Control Release. 138(3): 268-276 (2009)]. Low boiling point PFCs, such as perfluoropentane, also enable the use of lower acoustic amplitudes to generate ADV [Fabiilli et al., Ultrasound Med Biol. 36(8): 1364-1375 (2010)] and the production of stable gas bubbles in vivo [Kripfgans et al., IEEE Trans Ultrason Ferroelectr Freq Control. 49(2): 726-738 (2002); Kripfgans et al., IEEE Trans Ultrason Ferroelectr Freq Control. 52(7): 1101-1110 (2005); Zhang et al., Ultrasound Med Biol. 36(10): 1691-703 (2010)]. The ADV of PFC emulsions containing a lipophilic, therapeutic payload can be used to facilitate the delivery and release of the therapeutic agent, as demonstrated with in vitro [Fabiilli et al., Ultrasound Med Biol. 36(8): 1364-1375 (2010); Fang et al., Eur J Pharm Biopharm. 67(1): 67-75 (2007); Fang et al., Ultrasonics. 49(1): 39-46 (2009); Hwang et al., J Pharm Sci. 98(10): 3735-3747 (2009)] and in vivo [Rapoport et al., J Control Release. 138(3): 268-276 (2009)] studies.
The ADV of micron-sized PFC emulsions, administered intravenously or intraarterially, has also been used to generate localized, vascular occlusion in vivo [Kripfgans et al., IEEE Trans Ultrason Ferroelectr Freq Control. 49(2): 726-738 (2002); Kripfgans et al., IEEE Trans Ultrason Ferroelectr Freq Control. 52(7): 1101-1110 (2005); Zhang et al., Ultrasound Med Biol. 36(10): 1691-703 (2010)]. The temporal duration of an ADV-generated occlusion is transient, especially for gas emboli generated from intravenously administered emulsions [Zhang et al., Ultrasound Med Biol. 36(10): 1691-703 (2010)]. Therefore, the ability to extend this duration may be therapeutically beneficial for surgical applications that require longer occlusion times such as radiofrequency ablation [Arima et al., Int J Urol. 14(7): 585-590 (2007)] and high intensity focused US thermal therapy [Wu et al., Radiology. 235(2): 659-667 (2005)]. ADV-generated occlusion could also be potentially used to treat hemorrhaging associated with vascular damage or other internal bleeding, which are currently treated using transcatheter embolization [Charbonnet et al., Abdom Imaging. 30(6): 719-726 (2005); Petroianu, Dig Dis Sci. 52(10): 2478-2481 (2007)].
More recent work showed that PFC emulsions can serve as carriers for water-soluble therapeutic agents. The emulsions could be vaporized using US, thereby releasing the encapsulated agent from the emulsions via ADV [Fabiilli et al., Pharm Res. 27(12): 2753-2765 (2010)].